PROJECT SUMMARY My long-term professional goal is to become a successful, independent scientist with a research program focused on sex differences in the neurobiological response to exercise. Obesity continues to be a major health concern worldwide for both men and women. The vast majority of mechanistic studies on obesity therapeutics have been performed in men and male animals. The failure to include both sexes is problematic because the results of my pre-clinical experiments suggest that when examining the effect of exercise on food intake the results are sex specific. Leptin is an anorectic hormone produced by adipose tissue and communicates to the brain the state of peripheral tissue reserves. In males, exercise-induced increases hypothalamic leptin sensitivity and is thought to be, in part, responsible for an exercise-induced attenuation of food intake. In contrast, during weight regain, exercise fails to produce an attenuation of food intake in female rats. My working hypothesis is that estradiol (E2) blocks the exercise-induced enhancement of leptin sensitivity in females such that exercise supports intake compensation in the face of an acute exercise-induced increase in energy expenditure. To test this hypothesis in Aim 1, I will evaluate sex- and hormone-specific differences in exercise-induced changes in hypothalamic leptin sensitivity. The increase in hypothalamic leptin sensitivity in response to exercise seen in male rodents occurs through an interleukin (IL)-6 mechanism, however, this has yet to be characterized in females. Because it is known that E2 acting on estrogen receptor ? can inhibit inflammatory cytokine production including IL-6, I predict the presence of E2 inhibits the exercise- induced increase in IL-6 seen in male rodents. In Aim 2, I will measure hypothalamic and ventral tegmental area (VTA) IL-6 in female rats immediately following exercise then demonstrate that blockade or addition of IL- 6 will affect exercise-induced changes in leptin sensitivity. Exercise is thought to be an essential component of a weight loss maintenance strategy because it targets several maladaptive responses to weight loss. It is vitally important to understand how exercise alters energy homeostasis to facilitate weight loss maintenance as this new knowledge may contribute to the development of novel therapies that mimic these benefits of exercise. Moreover, my studies may reveal critical sex-specific differences in the benefits of exercise and explain why exercise might be a less effective weight loss strategy in women. The identification and characterization of these differences may have clinical implications with how we utilize exercise in conjunction with other behavioral strategies to facilitate weight loss maintenance.